ATP13A2 was first reported in relation to autosomal recessive Kufor-Rakeb syndrome in 2006 (Ramirez et al., PMID: 16964263). It was later reported in relation to other autosomal recessive neurodegenerative disorders including hereditary spastic paraplegia, cerebellar ataxia, amyotrophic lateral sclerosis (ALS), and neuronal ceroid lipofuscinosis. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there is insufficient evidence of a difference in molecular mechanisms or inheritance pattern to explain the wide phenotypic spectrum observed from ATP13A2 variation; therefore, the Intellectual Disability and Autism Gene Curation Expert Panel decided to lump all these entities together and curate them under the umbrella term Kufor-Rakeb syndrome.
Evidence supporting the relationship between ATP13A2 and a complex movement disorder includes case-level data, segregation data, and experimental data. For the purposes of this curation, nine variants (missense, splicing, nonsense, and frameshift) reported in seven probands in six publications are included in this curation: (PMIDs: 16964263, 21696388, 27165006, 31944623, 33033738, 30992063). In addition, variants in this gene segregated with disease in at least three families (PMIDs: 11584046, 16964263, 21696388). More genetic evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.
The mechanism of pathogenicity is known to be bi-allelic loss of function (LoF). This gene-disease association is also supported by animal models and in vitro functional assays (PMIDs: 22647602, 22442086, 23393156, 25855184, 30992063).
In summary, ATP13A2 is definitively associated with autosomal recessive Kufor-Rakeb syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on the meeting date April 14, 2022 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.